HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse.

AbstractOBJECTIVE:
Recently we showed that lack of the antioxidant enzyme glutathione peroxidase-1 (GPx1) accelerates atherosclerosis and upregulates proatherogenic pathways in diabetic apoE/GPx1-deficient double-knockout mice, thereby establishing GPx1 as an important therapeutic target. In vivo studies now investigate ebselen, a seleno-organic GPx1-mimetic, for its potential to reduce diabetes-associated atherosclerosis.
METHODS AND RESULTS:
Lesions were significantly increased in diabetic apoE(-/-) aortas (P<0.001) compared with nondiabetic controls after 20 weeks of diabetes. Ebselen-gavage significantly reduced total aortic lesions (P<0.001), with significant regional reductions in the arch (P<0.001), thoracic (P<0.001), and abdominal regions (P<0.05), but not within the aortic sinus of diabetic apoE(-/-) mice. These reductions were accompanied by significantly lower nitrotyrosine and Nox2 levels, reduced proatherogenic cellularity (macrophages and SMCs), and reduced expression of the proatherogenic mediator RAGE. Within the aortic sinus, ebselen reduced nitrotyrosine, Nox2, and VEGF levels but had no effect on RAGE. Studies in HAECs show that ebselen abrogates H(2)O(2)-induced increases in P-IKK, P-JNK, TNF-alpha, and Nox2.
CONCLUSIONS:
Ebselen reduces atherosclerotic lesions in most regions of diabetic apoE(-/-) aorta, except within the aortic sinus, suggesting its effectiveness as a potential antiatherogenic therapy in diabetic-macrovascular disease. Ebselen may elicit its effect via modulation of transcription factors such as NF-kappaB and AP-1.
AuthorsPhyllis Chew, Derek Y C Yuen, Philip Koh, Nada Stefanovic, Mark A Febbraio, Ismail Kola, Mark E Cooper, Judy B de Haan
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 6 Pg. 823-30 (Jun 2009) ISSN: 1524-4636 [Electronic] United States
PMID19325139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antioxidants
  • Apolipoproteins E
  • Azoles
  • Isoindoles
  • Membrane Glycoproteins
  • Organoselenium Compounds
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • 3-nitrotyrosine
  • ebselen
  • Tyrosine
  • Glutathione Peroxidase
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Glutathione Peroxidase GPX1
Topics
  • Administration, Oral
  • Animals
  • Antioxidants (administration & dosage, pharmacology)
  • Aorta, Abdominal (drug effects, metabolism)
  • Aorta, Thoracic (drug effects, metabolism)
  • Aortic Diseases (etiology, metabolism, pathology, prevention & control)
  • Apolipoproteins E (deficiency, genetics)
  • Atherosclerosis (etiology, metabolism, pathology, prevention & control)
  • Azoles (administration & dosage, pharmacology)
  • Cells, Cultured
  • Diabetes Mellitus, Experimental (complications, drug therapy, metabolism, pathology)
  • Diabetic Angiopathies (etiology, metabolism, pathology, prevention & control)
  • Endothelial Cells (drug effects, metabolism)
  • Glutathione Peroxidase (deficiency, genetics)
  • Humans
  • I-kappa B Kinase (metabolism)
  • Isoindoles
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Macrophages (drug effects, metabolism)
  • Male
  • Membrane Glycoproteins (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular (drug effects, metabolism)
  • NADPH Oxidase 2
  • NADPH Oxidases (metabolism)
  • Organoselenium Compounds (administration & dosage, pharmacology)
  • Phenotype
  • Phosphorylation
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic (metabolism)
  • Time Factors
  • Tumor Necrosis Factor-alpha (metabolism)
  • Tyrosine (analogs & derivatives, metabolism)
  • Vascular Endothelial Growth Factor A (metabolism)
  • Glutathione Peroxidase GPX1

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: